1. Field of the Invention
The present invention relates generally to an epigenetic marker indicative of cancer, and more specifically to the identification of a correlation of methylation-silenced transcription of SOCS-1 gene expression and cancer, and to reagents and methods for detecting and treating a cancer associated with methylation-silenced transcription of SOCS-1 gene expression.
2. Background Information
Cancer can occur due to contact with various etiologic agent, including, for example, exposure to environmental carcinogens or infection by a virus, or can be acquired congenitally from one or both parents. Such cancers have a genetic basis in that the changes responsible for the cancer are at the level of the nucleotide sequence of one or more genes in an individual. For example, some viruses have a life cycle that includes a stage in which it integrate into the nuclear genome of an organism such as a human. Where such integration results in disruption of a gene that is involved, for example, in instructing a cell to stop proliferating, the result can be unregulated proliferation of the cell, as is characteristic of some cancer cells.
In comparison, chemical carcinogens can cause physical damage to the DNA in an individual. Where the damage caused by the carcinogen is minimal, DNA repair mechanisms often can repair the damage such that the repaired sequence is identical to the sequence prior to the damage. Where the damage caused by the carcinogen is extensive, the cell containing the damaged DNA often dies. In some cases, however, the damage is not sufficient to kill the cell, but is too extensive to be repaired properly. In such cases, while the effort by the cell to repair the damaged DNA can be sufficient for the cell to continue growing and dividing, the repaired sequence is different from the DNA sequence prior to the damage. Where the defective repair occurs in a gene, the product of that gene may not be produced or, if the gene product is produced, it may not function properly. As such, where the normal gene product may, for example, regulate the time the cell normally would be destined to die, a cell lacking the normal gene product, as well as progeny of the cell, may continue to proliferate in an unregulated manner, as is characteristic of some cancer cells.
In addition to such genetic changes, cancer also can be caused by epigenetic mechanisms, which do not result in mutations of the DNA sequence. The most commonly observed epigenetic mechanism involves silencing of gene expression due to methylation of the gene sequence. Methylation of cytosine residues located 5′ to guanosine in CpG dinucleotides, particularly in CpG-rich regions (CpG islands), often is involved in the normal regulation of gene expression in higher eukaryotes. For example, extensive methylation of CpG islands is associated with transcriptional inactivation of selected imprinted genes, as well as the genes on the inactivated X chromosome in females. Aberrant methylation of normally unmethylated CpG islands also has been found in immortalized and transformed cells, and has been associated with transcriptional inactivation of defined tumor suppressor genes in human cancers.
Changes to genes that are associated with cancer, including mutations that result in loss of expression of gene or expression of a defective gene product, and epigenetic mechanisms such as methylation-silencing of gene transcription, provide markers useful for determining whether a cell is susceptible to loss of normal growth control and, therefore, potentially a cancer cell. For example, a mutation of the BRCA1 gene has been associated with breast cancer. As such, diagnostic tests can be performed using cells, for example, from a woman with a family history of breast cancer to determine whether the woman has the BRCA1 mutation that is a marker for breast cancer. The prostate specific antigen (PSA) is another example of a marker, in this case for prostate cancer. Although neither the defect resulting in expression of the PSA nor the normal function of PSA in the body is known, PSA nevertheless provides a valuable cancer marker because it allows the identification of men predisposed to prostate cancer or at a very early stage of the disease such that effective therapy can be implemented.
Cancer often is a silent disease that does not present clinical signs or symptoms until the disease is well advance. As such, the use of markers that allow the identification of individuals susceptible to a cancer, or even that allow detection of a cancer at an early stage, can be of great benefit. Unfortunately, such markers are not available for most cancers. As such, many cancer patients do not seek medical assistance until the cancer is at a stage that requires radical therapy, or is untreatable. Thus, a need exists for markers that can be used to detect cancer cells. The present invention satisfies this need and provides additional advantages.